Twin, adoption, and family studies have provided evidence that genes play an important role in alcohol and tobacco abuse. Moreover, epidemiological and biometrical genetics studies have shown that there is high comorbidity between alcohol and tobacco use, which may be due to overlapping genetic factors. Converging evidence from pharmacological research and the study of mouse models of alcohol- and tobacco-related phenotypes also supports the hypothesis that the same neurological pathways are activated by both substances. Recent evidence has implicated the neuronal nicotinic receptors (nAChRs) as critical targets of these drugs. Several nicotinic receptors are known to be involved in mediating the release of dopamine in response to alcohol and nicotine. These receptors (the alpha4-6 and beta2-3 subunits) may play an important role in regulating the dopaminergic reward pathway, which has been strongly implicated in contributing to the pleasurable feelings associated with substance use. This project seeks to examine the genes for the alpha4-6, beta2-3 nAChR subunits for their possible role in contributing to the development of alcohol and tobacco problem use. The candidate will examine these genes in a sample of sibling pairs for which DMA and phenotypic data have already been collected as a part of the National Longitudinal Study of Adolescent Health (Add Health). The candidate will utilize computational bioinformatics methods to identify potential functional single nucleotide polymorphisms (SNPs) within these genes in order to optimally select the SNPs and determine the genotypes of these in the subjects. Several statistical methods will be used to test for association and/or linkage with individual SNPs or haplotypes and alcohol or tobacco problem use. The skills to perform bioinformatics and statistical genetics will be developed through coursework, symposia, workshops, conferences, and consultations with mentors. Training will take place at the Institute for Behavioral Genetics, a unique environment where the candidate will have regular interactions with experts in behavior genetics and substance use disorders. This project will allow the candidate to achieve her short-term goals of learning computational bioinformatics methods, as well as advanced statistical genetics methods to analyze the data, while accumulating evidence that these genes may contribute to alcohol and tobacco problem use. It will also promote her long-term career goals of establishing an independent research career in behavior genetics of alcohol and tobacco use and provide a foundation for future studies.